nutrients

Review
Nutrigenetic Contributions to Dyslipidemia: A
Focus on Physiologically Relevant Pathways of Lipid
and Lipoprotein Metabolism
Bridget A. Hannon 1 , Naiman A. Khan 1,2 and Margarita Teran-Garcia 1,2,3, *
1 Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana-Champaign,
IL 61801, USA; bhannon3@illinois.edu (B.A.H.); nakhan2@illinois.edu (N.A.K.)
2 Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign,
Urbana-Champaign, IL 61801, USA
3 Department of Human Development and Family Studies, Cooperative Extension, University of Illinois at
Urbana-Champaign, Carle Illinois College of Medicine, Urbana-Champaign, IL 61801, USA
* Correspondence: teranmd@illinois.edu; Tel.: +1-(217)-244-2025




Received: 28 August 2018; Accepted: 27 September 2018; Published: 2 October 2018


Abstract: Cardiovascular disease (CVD) remains the number one cause of death worldwide, and
dyslipidemia is a major predictor of CVD mortality. Elevated lipid concentrations are the result of
multiple genetic and environmental factors. Over 150 genetic loci have been associated with blood
lipid levels. However, not all variants are present in pathways relevant to the pathophysiology of
dyslipidemia. The study of these physiologically relevant variants can provide mechanistic
understanding of dyslipidemia and identify potential novel therapeutic targets. Additionally,
dietary fatty acids have been evidenced to exert both positive and negative effects on lipid profiles.
The metabolism of both dietary and endogenously synthesized lipids can be affected by individual
genetic variation to produce elevated lipid concentrations. This review will explore the genetic,
dietary, and nutrigenetic contributions to dyslipidemia.

Keywords: dyslipidemia; nutrigenetics; lipids

1. Introduction
Elevated blood lipid concentrations, or dyslipidemia, currently affect 13% of the US population,
and are strong predictors of cardiovascular disease (CVD) [1]. Dyslipidemia can be diagnosed by
the presence of one or more of the following phenotypes: elevated concentrations of total cholesterol
(TC), low-density lipoprotein cholesterol (LDL), and triglycerides (TG), or low concentrations of
high-density lipoprotein cholesterol (HDL) [2]. Dyslipidemia is a complex disease that is the result of
multiple biological and behavioral etiologies, such as genetic predisposition, metabolic capacity, dietary
intake, and physical activity [3]. Understanding the interactions between these complex factors to
produce phenotypes of dyslipidemia is crucial to identifying and implementing successful strategies to
manage blood lipids. Among biological factors, the study of genetics is essential to improving
scientific understanding of disease progression at its most basic level and understanding of the role of
individual genetic variation in disease predisposition can lead to improvements in identification
and prevention of disease in genetically at-risk individuals. Of the many behavioral contributors to
dyslipidemia, diet offers one of the most efficacious behavioral approaches to disease prevention, and
it is a crucial determinant of maintenance of health throughout the lifespan [4]. The role of dietary fat
intake in exacerbation or amelioration of CVD risk has been a topic of debate in the field of nutrition.
Dietary fatty acids are a heterogeneous group of nutrients, and their varying molecular properties,
as well as the food matrix in which they reside, exert differential effects on blood lipids. The intake and

Nutrients 2018, 10, 1404; doi:10.3390/nu10101404 www.mdpi.com/journal/nutrients

Nutrients 2018, 10, 1404 2 of 17

metabolism of various fatty acids may be influenced by individual genetic variation. These biological
and behavioral factors must be considered not as individual risk factors, but as interacting elements.
The following review of the literature will present a summary of the recent work conducted to better
elucidate the role of both biological (genetic) and behavioral (dietary) influences on dyslipidemia, and
the interactions of these components in the clinical intervention setting.

2. Pathophysiology of Dyslipidemia
Elevated TG and decreased HDL concentrations are metabolic consequences of excess visceral
adipose tissue and increase risk of atherosclerotic disease through various mechanisms. The role of
elevated TG concentrations in CVD progression is not fully elucidated, but it has been postulated to be
due to increased endothelial activation and inflammation [5]. Elevated TG concentrations are strongly
associated with insulin resistance, CVD, and other indicators of metabolic dysfunction, due to
excess adipose tissue mass [6,7]. A hypertriglyceridemic state promotes the exchange of TG from
very-low density lipoprotein (VLDL) for cholesterol esters from LDL and HDL particles, creating small,
lipid-poor particles. Small HDL particles are more susceptible to degradation, thus contributing to
the low HDL concentrations observed in the presence of other dyslipidemias [8]. Elevated HDL
concentrations are generally recognized as cardioprotective, as these lipoproteins serve to sequester
excess cholesterol to the liver for excretion. Low concentrations of HDL are a diagnostic biomarker for
both the Metabolic Syndrome (MetS) and CVD. The relationship between elevated HDL and metabolic
disease has been challenged by results from clinical trials with HDL-raising agents, which did not lead
to reduction in cardiovascular events compared to the control group [9]. However, due to the strong
inverse relationship between HDL concentrations and CVD at the epidemiological level, it remains a
key biomarker for assessing cardiometabolic health [10].

3. Genetic Contributions to Dyslipidemia

With the exception of rare genetic mutations, the majority of dyslipidemias are secondary to
other metabolic abnormalities, including abdominal obesity [6]. When describing the complex genetic
components of dyslipidemia, one can distinguish between monogenic and polygenic traits. Monogenic
diseases are the result of a single mutation in one gene, resulting in a severe phenotype. Some classic
examples of these monogenic conditions include Tangier disease (resulting in severely low HDL),
LDL receptor deficiency (characterized by elevated LDL concentrations), familial chylomicronemia
or lipoprotein lipase (LPL) deficiency (causes severe hypertriglyceridemia) and other familial
hypercholesterolemias [11–13]. Table 1 presents summary of selected monogenic lipid disorders.
These monogenic conditions produce a severe effect, but the frequency of these risk alleles in the
population is considerably low. The common variants that produce smaller phenotypic effects
contribute to the polygenic nature of obesity and dyslipidemia. These common variants, specifically
the single nucleotide polymorphisms (SNPs), are present in at least 1% of the population, and the
phenotypic effect of these SNPs individually is not likely to be observed. The differences in phenotypic
effect and allele frequency between rare and common variances are represented in Figure 1. Monogenic
conditions are represented on the left side of the graph, where the phenotypic effect is very severe,
but the frequency is low. The common variants fall on the middle and right side of the graph,
with variants exerting a small phenotypic effect that is not deleterious and are present in high frequency
in the population. On their own, these variants cannot result in a pronounced phenotype, but the
co-occurrence of many of these common variants may cumulatively increase genetic risk for these
diseases. Dyslipidemia and atherosclerosis are complex phenotypes, and thus the genetic component of
these disease is also the result of complex interactions between various metabolic pathways [14].
Nutrients 2018, 10, x FOR PEER REVIEW 3 of 17

Table 1. Monogenic disorders affect blood lipid concentrations (not an extensive list).
Nutrients 2018, 10, 1404 3 of 17
Phenotype Disorder Gene Affected Prevalence
Hyperlipoproteinemia Type 2A LDLR 0.2%
High LDL
Table 1. Monogenic
Autosomal Dominantdisorders affect blood lipid PCSK9,
Hypercholesterolemia concentrations
APOE (not an extensive list).
0.5%
Tangier Disease ABCA1 <100 cases reported worldwide
LowPhenotype
HDL Disorder Gene Affected Prevalence
Familial LCAT deficiency LCAT 70 reported cases
Hyperlipoproteinemia Type
Familial Chylomicronemia 2A LDLR
LPL, APOC2 0.2%
<0.0001
High LDL
High TG Autosomal Dominant Hypercholesterolemia PCSK9, APOE 0.5%
Severe Hypertriglyceridemia APOA5, LMF1 <0.5%
Tangier Disease ABCA1 <100 cases reported worldwide
TableLow
adapted
HDL from Dron and Hegele [15]. LDL, low-density lipoprotein cholesterol; HDL, high-
Familial LCAT deficiency LCAT 70 reported cases
density lipoprotein cholesterol; TG, triglycerides;
Familial Chylomicronemia
LDL-R, LDL
LPL, APOC2
receptor; PCSK9,
<0.0001
proprotein
High TG
convertase subtilisin/kexin type
Severe 9; APOE, apolipoproteinAPOA5,
Hypertriglyceridemia E; ABCA1,
LMF1 adenosine triphosphate
<0.5% (ATP)
bindingTable
cassette
adaptedsubfamily A member
from Dron and 1;LDL,
Hegele [15]. LCAT, lecithin-cholesterol
low-density acyltransferase;
lipoprotein cholesterol; LPL,lipoprotein
HDL, high-density lipoprotein
cholesterol; TG, triglycerides; LDL-R, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9;
lipase; APOC2, apolipoprotein
APOE, apolipoprotein C2;adenosine
E; ABCA1, APOA5,triphosphate
apolipoprotein A5; LMF1,
(ATP) binding cassettelipase maturation
subfamily A memberfactor 1.
1; LCAT,
lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; APOC2, apolipoprotein C2; APOA5, apolipoprotein A5;
LMF1, lipase maturation factor 1.
These polygenic, common variants associated with dyslipidemia have been identified through
genome-wide association studies (GWAS). Over 150 loci have been specifically associated with blood
These polygenic, common variants associated with dyslipidemia have been identified through
lipid concentrations (total cholesterol
genome-wide association (TC), TG,
studies (GWAS). Over HDL,
150 lociand
haveLDL) in European
been specifically populations
associated [16,17].
with blood
Notably, several
lipid of the identified
concentrations variants(TC),
(total cholesterol wereTG,in biologically
HDL, and LDL) andinclinically
Europeanrelevant genes,
populations such as
[16,17].
angiopoietin-like proteins
Notably, several of the3identified
and 4 (ANGPTL3/4),
variants were inhibitors of LPL,
in biologically and HMGCR,
and clinically relevantwhich
genes,codes
such asfor 3-
hydroxy-3-methylglutaryl-CoA
angiopoietin-like proteins 3reductase, a target for
and 4 (ANGPTL3/4), statin therapy
inhibitors andHMGCR,
of LPL, and the rate-limiting enzyme
which codes for in
3-hydroxy-3-methylglutaryl-CoA reductase, a target for statin therapy and the rate-limiting
cholesterol synthesis. GWAS are a powerful and hypothesis-generating tool that can identify loci that enzyme
in cholesterol
are associated withsynthesis. GWASof
phenotypes aredyslipidemia,
a powerful and research
hypothesis-generating tool that
into the effects of can
theidentify loci
physiological
that are associated with phenotypes of dyslipidemia, research into the effects of the physiological
relevance and implication of functional variants in dyslipidemia phenotypes will further increase the
relevance and implication of functional variants in dyslipidemia phenotypes will further increase the
understanding of this complex disease.
understanding of this complex disease.

More Severe
Phenotypic Effect

Less Severe

Less Common More Common

Minor Allele Frequency

Figure 1. Graphic representation of phenotypic effects of rare versus common variants. Rare variants,
such
Figure 1. as monogenic
Graphic disorders,
representation of fall on the left
phenotypic of theofgraph.
effects Common
rare versus variants
common with a less
variants. Raresevere
variants,
phenotypic effects are on the right.
such as monogenic disorders, fall on the left of the graph. Common variants with a less severe
phenotypic
3.1. Focus effects are on the
on Physiological right.
Relevance
Not all associated common variants are in physiologically relevant pathways, and therefore cannot
3.1. Focus on Physiological Relevance
provide insight into the mechanisms by which nutrients interact with metabolic processes to produce
phenotypes
Not of dyslipidemia.
all associated common In the pathophysiology
variants and progression
are in physiologically of atherogenic
relevant pathways,dyslipidemia,
and therefore
relevant pathways can include reverse cholesterol transport, cellular lipid uptake, and
cannot provide insight into the mechanisms by which nutrients interact with metabolic processes tolipoprotein
formation. The interactions of these pathways are depicted in Figure 2.
produce phenotypes of dyslipidemia. In the pathophysiology and progression of atherogenic
dyslipidemia, relevant pathways can include reverse cholesterol transport, cellular lipid uptake, and
lipoprotein formation. The interactions of these pathways are depicted in Figure 2.
Reverse cholesterol transport (RCT) facilitates the return of excess cholesterol from peripheral
tissues to the liver to be excreted from the body as bile [18]. Key proteins in this pathway include
Nutrients 2018, 10, 1404 4 of 17

Reverse cholesterol transport (RCT) facilitates the return of excess cholesterol from peripheral
tissues to the liver to be excreted from the body as bile [18]. Key proteins in this pathway include
ATP-binding cassette subfamily A member 1 (ABCA1), cholesterol-ester transfer protein (CETP),
apolipoprotein A1 (APOA1), hepatic lipase (HL, gene name: LIPC), and lecithin: cholesterol
acyltransferase (LCAT), which serve to regulate concentrations of HDL and TG in circulation. Altered
functionality of the RCT pathway can lead to decreased HDL concentrations, as fewer cholesteryl
ester particles are accumulated within HDL particles [19]. SNPs in these genes have been previously
associated with blood lipids in various populations. ABCA1 is essential in the efflux of cholesterol
from peripheral tissues, and complete knockout of this protein results in Tangier disease. However,
this gene contains several common polymorphisms that have been associated with HDL [20] and
TG concentrations [21]. Mirmiran et al. recently described the gene-diet interactions of five CETP
variants in observational and intervention studies [22]. These authors reported significant interactions
between CETP genotype and dietary components, including alcohol and fat intake, to associate with
blood lipid profiles. Interestingly, Nakamura et al. has reported evidence for the combined effects of
multiple SNPs in the ABCA1 and CETP genes, suggesting a more significant genetic contribution to
blood lipid concentrations when these variants are considered together, rather than on their own [23].
APOA1 is the predominant apolipoprotein on HDL particles and essential in RCT function and HDL
formation. Variants in this gene have been associated with blood lipids in both European and Chinese
populations [16,24]. HL is involved in the remodeling of HDL particles, and thus facilitates RCT [25].
Polymorphisms in the coding and promotor regions of LIPC have been identified through GWAS, and
subsequently studied for associations with blood lipids in diverse populations [26,27]. SNPs in LIPC
have also been implicated in affecting lipid response to weight loss interventions [28]. The effect of LIPC
polymorphisms on blood lipids is more well-defined compared to other genes in this pathway, due to
the extensive body of evidence conducted on this gene. LCAT is another protein involved in HDL
maturation, as it is responsible for synthesis of cholesteryl ester in plasma. Due to its functional role in
RCT, it is logical that the majority of candidate gene studies have focused on HDL as the phenotypic
outcome of interest. Significant associations have been detected between LCAT polymorphisms and
HDL in clinical populations, but there is not substantial evidence to definitively conclude that variants
in this gene strongly impact blood lipid concentrations [29].
Cellular lipid uptake refers to the movement of dietary or endogenously produced lipids and
lipoproteins through circulation, peripheral tissues, and the liver [30,31]. Key proteins in this
pathway include lipoprotein lipase (LPL), LDLR, ANGPTL3/4, and fatty acid translocase (cluster of
differentiation 36, CD36). LPL is present on cellular membranes and is involved in the lipolysis of
TG in lipoproteins to fatty acids. Several common variants in the LPL gene have been associated
with blood lipids, including a gain-of-function mutation that is associated with TG concentrations
in European, but not African, populations [32]. Several SNPs have also been associated with HDL
concentrations and high-fat diet [33], indicating the importance of this protein in the metabolism of
dietary and endogenous lipids. LDLR is expressed primarily in hepatocytes, and polymorphisms in
this gene can affect protein functionality, splicing, or transcription. Associations between variants
in LDLR and adverse blood lipid concentrations have been detected in GWAS [34], and one variant,
rs688, has been studied in vitro to determine the mechanistic consequences of this polymorphism on
altered protein functionality [35]. ANGPTL 3 and 4 inhibit LPL in cardiac and skeletal muscle and
adipose tissue, preventing the lipolysis and removal of TG from circulation. ANGPTL3 expression also
results in lower LDL production through increased clearance of ApoB-containing lipoproteins [36].
ANGPTL4 is induced in the fasting state, allowing for increased delivery of fatty acids to tissues
other than adipose. Genetic associations between variants in ANGPTL4 and both LDL [16] and HDL
concentrations [37] have been reported in European populations. The consequences of ANGPTL
variants on dyslipidemia was recently summarized by Paththinige et al. [38]. CD36 is involved in
the cellular uptake of both dietary and endogenous lipids, and variants in the CD36 gene were first
associated with blood lipids by Ma et al. [39]. Mechanistically, CD36 is a logical target for gene-diet
Nutrients 2018, 10, 1404 5 of 17

interaction studies, and polymorphisms have been associated with blood lipids in diverse populations
with [40] and without the inclusion of dietary intake [41].
The endogenous synthesis and export of lipids and lipoproteins from the liver also has clinical
relevance in dyslipidemia and obesity, as excess energy intake can upregulate these processes [42,43].
Common variants in these pathways can alter the functionality of encoded proteins, resulting in
metabolic alterations and phenotypic traits such as dyslipidemia [44]. Genetic variants present in genes
coding for apolipoproteins also have been evidenced to impact risk of dyslipidemia and atherosclerotic
disease. The most classic example is APOE, coding for apolipoprotein E (APOE). APOE circulates
on lipoproteins in both systemic circulation and the central nervous system. The isoforms of this
gene affect the affinity of APOE to its binding protein, and the E4 genotype has been associated
with increased CVD risk and elevated blood lipid levels, and has been summarized previously [45].
Genes coding for other apolipoproteins also contain common variants previously been associated with
blood lipids and have functional relevance for dyslipidemia, such as APOA5 and APOA2. Variants in
APOA5 have been evidenced to significantly impact TG concentrations and were recently summarized
by Guardiola and Ribalta [46]. APOA2 is also associated with HDL, and variants in this gene have been
evidenced to interact with dietary fat intake to affect inflammatory status among individuals with
diabetes, although the mechanism remains to be elucidated [47,48]. Regarding endogenous lipogenesis,
key proteins include fatty acid desaturase (FADS) and peroxisome-proliferator activator receptor
alpha (PPARA). Genes in the FADS cluster (FADS1, FADS2, FADS3) code for proteins responsible
for desaturation of dietary and endogenous lipids, and variants in these genes have been associated
with circulating polyunsaturated fatty acid (PUFA) concentrations, as it is postulated that presence of
certain polymorphisms results in decreased functionality of the enzymes [49–51]. Additionally, we
and others have published on the associations between FADS SNPs and blood lipids [52,53]. PPARA
regulates a host of lipid and glucose homeostatic processes in the liver, and as PUFAs are ligands
for all PPAR isoforms, these genes are targets for gene-diet interaction studies [54]. Variants in
PPARA have been evidenced to influence blood lipid concentrations in the context of a high-fat
diet [55,56]. Regarding nutritional control of hepatic TG synthesis, max-like protein X (MLX) interacting
protein like (MLXIPL) induces these pathways in a carbohydrate-dependent manner (an alias for
MLXIPL is carbohydrate-response element binding protein, ChREBP). Variants in MLXIPL have been
examined as a mechanism for elevated TG concentrations, and associations have been detected in a
Chinese population [57]. However, there are other transcriptional regulators of lipid synthesis, such
as sterol-regulatory element binding protein 1 (SREBP1) and upstream transcription factor (USF),
that have not been extensively explored in genetic associations. The study of pathways involved in
blood lipid concentrations is necessary to better understand of the biological aspects of dyslipidemia
and potentially identify new targets in specific proteins or pathways to develop preventative and
treatment therapies.

3.2. Differences in Minor Allele Frequency and Special Populations

The majority of genetic association studies have been conducted among individuals of European
descent; as of 2011, only 4% of GWAS had been conducted in non-European populations [58]. Evidence
from genetic association studies in non-European populations have concluded that findings from one
study may not always apply to other populations. Examples of this include differences in minor allele
frequency (MAF) across populations, differences in risk allele, and discovery of novel candidate loci.
The study of genetic associations with dyslipidemia is necessary to better understand the biological
reasons for increased disease prevalence among certain ethnic groups. The Mexican population has
one of the highest prevalence of dyslipidemias, with low HDL and elevated TG concentrations affecting
61% and 32% of the adult population, respectively [59]. The following examples highlight some of the
genetic studies in this population and the need for further study of the genetic and environmental basis
for the disproportionate rates of dyslipidemia. The differences in MAF have been highlighted by the
1000 Genomes Project, and have informed databases such as the dbSNP database of National Center for
 Nutrients 2018, 10, 1404 6 of 17

Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/snp) [60]. One such example of

major differences in MAF and CVD risk is rs1800588 (LIPC). This SNP has a global MAF of 0.39, but is
Nutrients 2018, 10, x FOR PEER REVIEW 6 of 17
as high as 0.50 in Mexican populations (1000 Genomes). The rs1800588 genotype has been associated
with TG concentrations among Mexican adults [61]. The current MAF and risk allele definitions for
individuals living in Los Angeles, United States (US). This is not a large enough sample to generalize
Mexican populations that come from the 1000 Genomes Project is from 107 individuals living in Los
for the entire Mexican population in both the US and Mexico. Our group has published on a larger
Angeles, United States (US). This is not a large enough sample to generalize for the entire Mexican
cohort study of almost 1000 individuals from Mexico, and have detected differences in minor and
population in both the US and Mexico. Our group has published on a larger cohort study of almost 1000
risk alleles for SNPs in the FADS cluster [53]. Furthermore, a recent GWAS conducted in Mexicans
individuals from Mexico, and have detected differences in minor and risk alleles for SNPs in the FADS
identified novel genetic loci to be associated with TG concentrations [62]. These variants had not been
cluster [53]. Furthermore, a recent GWAS conducted in Mexicans identified novel genetic loci to be
identified in previous
associated studies, thus emphasizing
with TG concentrations the need
[62]. These variants hadfor
notfurther investigation
been identified into the
in previous genetic
studies,
effects
thusof dyslipidemia
emphasizing thein thisfor
need understudied, at-risk group.
further investigation The
into the lack of
genetic diversity
effects in genomicin
of dyslipidemia research
this
is limiting
understudied, at-risk group. The lack of diversity in genomic research is limiting the implementation of of
the implementation of precision medicine and nutrition recommendations for people
diverse ethnicities
precision medicine [63].
and nutrition recommendations for people of diverse ethnicities [63].
The lack
The of reproducibility
lack among
of reproducibility amonggenetic association
genetic studies
association is particularly
studies problematic
is particularly for diverse
problematic for
populations. These ethnic
diverse populations. subgroups,
These such as Hispanic
ethnic subgroups, such as and African-Americans,
Hispanic have some
and African-Americans, of the
have somehighest
of
prevalence of prevalence
the highest dyslipidemia and other chronic,
of dyslipidemia non-communicable
and other diseases in diseases
chronic, non-communicable the US [64].
in theThe
US results
[64].
fromThegenetic
resultsassociation
from geneticstudies
association studiesin
conducted conducted
populationsin populations
of European of ancestry
Europeanmay ancestry may not to
not translate
translate
these diverseto these diverse populations,
populations, delaying thedelaying
benefit the
thatbenefit
these that these individuals
individuals might receive
might receive as
as medicine
medicine
moves towardmovesthe toward theofdirection
direction of personalized,
personalized, genotype-based
genotype-based recommendations.
recommendations.

Figure
Figure2. 2.Physiologically relevant
Physiologically genes
relevant of lipid
genes and and
of lipid lipoprotein metabolism
lipoprotein metabolism pathways.
pathways. CM,
chylomicron; HDL, high-density lipoprotein; IDL, intermediate density lipoprotein;
CM, chylomicron; HDL, high-density lipoprotein; IDL, intermediate density lipoprotein; LDL, low-density
lipoprotein; VLDL, very-low
LDL, low-density density
lipoprotein; lipoprotein;
VLDL, very-low ABCA1, ATP-bindingABCA1,
density lipoprotein; cassetteATP-binding
transported cassette
subfamily
A transported
member 1; ANGPTL3/4,
subfamily A angiopoietin-like
member 1; ANGPTL3/4,proteins angiopoietin-like
3 & 4; APOA1, proteins
apolipoprotein
3 & 4;AI; APOA2,
APOA1,
apolipoprotein
apolipoprotein AII;AI; APOA2,apolipoprotein
APOAV, apolipoproteinAV; APOAV,
AII;APOE, apolipoprotein
apolipoprotein E;AV; APOE,
CD36, apolipoprotein
cluster E;
of differentiation
CD36, cluster of differentiation 36 (fatty acid translocase); CETP, cholesterol esterase
36 (fatty acid translocase); CETP, cholesterol esterase transfer protein; FADS, fatty acid desaturase transfer
protein;
cluster; FADS, MLX
MLXIPL, fatty acid desaturase
interacting protein like;MLXIPL,
cluster; MLX interacting
LCAT, lecithin, cholesterol protein like; LCAT,LDLR,
acyltransferase; lecithin,
LDL
cholesterol acyltransferase; LDLR, LDL receptor; LIPC, hepatic lipase; LPL, lipoprotein
receptor; LIPC, hepatic lipase; LPL, lipoprotein lipase; PPARA, peroxisome-proliferator activator lipase; PPARA,
peroxisome-proliferator activator receptor alpha.
receptor alpha;.

4. Dietary Contributions to Dyslipidemia

Dietary intake has a crucial role in affecting metabolic health and disease risk. Dietary components
that have been previously implicated in increasing blood lipid concentrations include alcohol,
carbohydrates, and dietary fat. The role of alcohol [65] and carbohydrates [66] have been previously
reviewed; therefore, the current review will focus on dietary fat. Currently, agencies such as the
American Heart Association (AHA), the Department of Agriculture, and the Department of Health
Nutrients 2018, 10, 1404 7 of 17

4. Dietary Contributions to Dyslipidemia

Dietary intake has a crucial role in affecting metabolic health and disease risk. Dietary components
that have been previously implicated in increasing blood lipid concentrations include alcohol,
carbohydrates, and dietary fat. The role of alcohol [65] and carbohydrates [66] have been previously
reviewed; therefore, the current review will focus on dietary fat. Currently, agencies such as the
American Heart Association (AHA), the Department of Agriculture, and the Department of Health
and Human Services to recommend the limiting of total and saturated fat (SFA) [2,67]. However,
the recommendation of a low-fat diet for heart health was challenged when researchers from the
Seven Countries Study observed a low prevalence of CVD in the Mediterranean region, despite the
consumption of a diet containing a moderate amount of total fat, coming from olive oil and cold-water
fish [68,69]. This led to several seminal clinical trials to explore the effects of the Mediterranean diet on
CVD risk and mortality, such as the Lyon Heart Study and PREDIMED [70,71]. The promising results of
these trials have led to further scientific exploration of differential effects of various types of dietary
fatty acids in ameliorating or exacerbating CVD risk. The replacement of saturated for unsaturated fat
in the diet has been evidenced to be lipid-lowering and protective against CVD [72,73].
Unsaturated fats, those present in high amounts in the Mediterranean diet described above, are
classified into monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. MUFAs are present
in foods such as avocados, almonds and other nuts, and vegetable oils. MUFAs are cardioprotective in
that they do not raise blood lipid concentrations, and are less susceptible to oxidation than are PUFAs,
due to their lower degree of unsaturation [74]. MUFAs are also more effective than carbohydrates in
reducing blood lipid concentrations when replaced for SFA in the diet [75]. The majority of studies
examining MUFA intake and blood lipids have been conducted concurrently with consumption of a
Mediterranean diet, which has been associated with lower TG concentrations in meta-analyses [76,77].
However, as there are additional dietary components present in a Mediterranean diet, such as fiber,
micronutrients, phytochemicals, and PUFAs, it is difficult to elucidate the specific effects of MUFAs
alone on blood lipids. The effects of PUFA intake, present in cold-water fish, walnuts, and corn oil,
on blood lipids and CVD risk have been studied extensively [78]. Intake of n-3 and n-6 PUFAs have
both been associated with decreased CVD risk, especially the n-3 series, as they have been evidenced to
have anti-arrhythmic and potent TG-lowering effects [79]. N-3 PUFA supplementation is currently
recommended by the AHA to prevent recurrence of myocardial infarction [80].
The mechanisms by which unsaturated fatty acids affect blood lipid profiles have been previously
summarized [70,72,74,81]. In brief, PUFA can serve to upregulate mRNA and thus protein levels of
LDL receptors, resulting in increased lipoprotein uptake to the liver [82]. PUFA also downregulate fatty
acid synthase, a key step in de novo lipogenesis, and very-low density lipoprotein (VLDL) secretion
from the liver [83]. MUFA has been associated with decreased apolipoprotein C-III, which is an
activator of LPL [84]. Clinical studies have also shown the effects of MUFA intake on decreasing
apoB-100 production, the primary apolipoprotein present on circulating VLDL [81].
The lipid and lipoprotein response to intake of these various fatty acids may not be consistent
among different populations studied. The reasons for this variability can be due to age, sex, disease
state, differences at the genetic level, or any combination of these factors. The role of individual genetic
variation in determining differential phenotypes has become more clearly understood, as advances in
genetic technology and large cohort studies have identified significant associations between dietary
intake and genetic variants to produce differences in disease risk [85]. The field of nutrigenomics refers
broadly to the study of the interactions between dietary intake and the genome [86]. These interactions
can result in epigenetic modification of genes, transcriptional regulation, or alterations in protein
functionality. A subset of nutrigenomics is nutrigenetics, which specifically examines the effect of
individual genetic variants (i.e., SNPs) and dietary intake on phenotypic expression. The exploration of
these interactions can direct the creation of personalized recommendations for consumption of certain
dietary fatty acids for the maintenance of normal lipid profiles and achievement of a healthy weight.
Nutrients 2018, 10, 1404 8 of 17

5. Nutrient-Gene Interactions and Dyslipidemia

Nutrigenetics, the science of the effect of genetic variation on response to dietary intake, bridges
the gap between biological (genetic) and behavioral (diet) factors contributing to complex diseases,
and can offer explanation as to why researchers may observe differential effects among individuals fed
identical diets. Knowledge gained from this field is promising, as it can lead to explanation of response
variability in clinical trials with diverse populations, better identification of non-responders to various
diets, and the development of personalized dietary strategies [87].
As dyslipidemia is the result of a combination of genetic and environmental factors, it is logical that
these two elements be examined in conjunction with one another. As many genetic loci associated with
dyslipidemia have already been identified, the next step is to identify gene-environment interactions
that may exacerbate or ameliorate the effect of genetic variation on disease risk. The integration of
environmental exposures, especially dietary intake, may be able to add to the understanding of
the complex etiologies associated with dyslipidemia. Furthermore, a targeted approach through
the selection of physiologically relevant genes involved in pathways of lipoprotein metabolism and
atherosclerosis will yield important discovery into the biology behind how these proteins metabolize
nutrients in the presence of genetic mutations [14].
Previous research conducted to further classify the effects of common variants and dietary fat
intake on lipid profiles has provided initial evidence of the need for deeper understanding in this
field. Current literature on gene-diet interactions of physiologically relevant genes and dietary fat
intake is presented in Table 2. A classic example, from Ordovas et al. examined the interactive
effects of a polymorphism in the promotor region (rs1800588) of the LIPC gene and total fat intake [88].
This polymorphism has been associated with decreased activity of hepatic lipase. Mutations in
this enzyme can result in elevated TG. Results indicated that rs1800588 genotype was significantly
associated with HDL concentrations, and this association was strengthened when dietary intake was
also considered. The interaction between presence of the risk allele and fat intake greater than 30% of
total calories was associated with increased HDL, suggesting that these individuals may benefit from
a high fat diet, specifically one high in MUFAs [89]. A diet high in total fat, defined in a study by
Sanchez-Moreno et al. as consumption greater than 98 grams per day (the study median), did not
associate with significantly higher TG concentrations by APOA5 (rs662799) genotype, indicating
there was no disadvantage to this mutation in individuals’ ability to metabolize a high-fat diet [90].
These studies indicate that a high-fat diet may be beneficial in maintaining desired blood lipid
concentrations for individuals possessing the minor alleles of common variants.
The nutrigenetic interactions between n-3 PUFA intake and common variants in genes related to
atherosclerosis are summarized by Merched and Chan [91]. PUFA intake has been evidenced to interact
with a polymorphism in PPARA, a transcriptional regulator of lipid metabolism, to associate with lower
TG concentrations among those consuming high PUFA intake [92]. Several variants in APOA5, coding
for apolipoprotein AV, have been evidence to interacte with PUFA intake to associate with elevated TG
concentrations in individuals possessing the risk allele [93]. However, the APOA5 gene has 14 known
SNPs listed on the NCBI database alone, so it is quite possible that these variants may interact with
one another, or other genetic or non-genetic factors, to affect response to dietary intervention.
As we recognize the need to translate basic science into clinical applications, individual genetic
variants have been studied as predictors of the lipid response to dietary interventions among
individuals with obesity [94,95]. Several studies have specifically examined the role of physiologically
relevant variants on changes in lipid profiles, with promising results. Zhang et al., studied the role of
the rs964184 variant (APOA5) on modifying changes in TC, HDL, and LDL after the POUNDS LOST
(Preventing Overweight Using Novel Dietary Strategies) weight loss trial, in which participants were
randomized to follow one of four diets of varying macronutrient composition [96]. However, the
POUNDS LOST dietary conditions varied in total fat content, and the researchers did not account for
the dietary fat composition (SFA, MUFA, PUFA) of the diets. The type and amount of dietary fat intake
is evidenced to interact with genetic variants to influence blood lipid profiles [97–100].
Nutrients 2018, 10, 1404 9 of 17

The gene-diet interactions of cholesterol metabolism were reviewed by Abdullah et al., in

2015 [101]. These researchers focused their review on the outcomes of TC, LDL, and HDL
concentrations and any dietary exposure. This review provides strong evidence for the role of
variants in over 20 genes involved in cholesterol metabolism. Nuno et al. recently reviewed the
literature on variants in genes involved in lipid metabolism and dietary intake on CVD risk [102].
Many of the studies reported in this review describe significant associations with variants in several of
the genes mentioned, blood lipids, and dietary intake of carbohydrates and various fatty acids.
One notable limitation in these reviews is the limited research on dietary patterns, rather than
consideration of macronutrient intake alone. As nutrients are not consumed in isolation, the study of
the interacting effects of different dietary components, as in a Mediterranean diet, with individual
genetic variation on disease risk is a promising direction for future study. Additionally, as fatty acids
are heterogeneous, there must be more research on the interacting effects between different classes of
fatty acids (medium- to long-chain, degree of saturation, etc.) and the foods they are present in and
genetic variation. A relevant example of this is dairy fat. Dairy consumption has been associated
with protective benefits against T2DM, obesity, and other cardiometabolic biomarkers [103,104].
A recent longitudinal study of over 2000 adults concluded that circulating levels of the fatty acids
present in dairy products (pentadecanoic, heptadecanoic, and trans-palmitoleic) were not associated
with mortality, but were associated with lower risk of CVD mortality [105]. More research into the
effects of various foods high in SFA on risk factors for metabolic diseases are warranted, as these fatty
acids are not consumed in isolation, and even foods high in SFA contain some degree of unsaturated fat.
These nutrient-gene interactions only represent a portion of the functional variants that have been
associated with blood lipids in GWAS. Nevertheless, additional research is necessary, especially in
diverse or minority populations across the lifecycle, to further elucidate the mechanisms by which diet
can interact with genetic variation. The ultimate goal of this field of research is the translation of these
discoveries into personalized nutrition recommendations to treat and prevent disease [106].

6. Conclusions
The genetic, dietary, and nutrigenetic components described here highlight the strong
relationships between biological and behavioral risk factors for dyslipidemia. The exploration of
physiologically relevant variants and their interactions with dietary lipids is especially pertinent to the
development of personalized dietary recommendations for management of dyslipidemia. As obesity, a
major risk factor for the development of dyslipidemia, continues to increase in prevalence worldwide,
effective strategies to achieve a healthy weight and manage lipid profiles are needed. Due to genetic
variation, among other factors, not all individuals will respond uniformly to these strategies. Thus,
the identification of factors that explain this variability in response will provide researchers and
clinicians with the information to apply targeted treatment approaches to maximize benefits against
dyslipidemia. Understanding the biological reasons behind why an individual may not respond is a
key research priority to be addressed, as this can lead to implementation of individualized nutrition
recommendations that can be implemented to prevent and treat dyslipidemia [107].
Nutrients 2018, 10, 1404 10 of 17

Table 2. Summary of gene-diet interactions between physiologically relevant variables of lipid and lipoprotein metabolism and dietary fat intake associated with
blood lipids.

Previous Nutrient-Gene Interaction Risk MAF

Gene Locus Protein Function SNP Function of Variant
with Blood Lipids Allele Global
Reverse Cholesterol Transport Pathway
Facilitates the exchange of cholesterol esters for Total fat and TG [98]; total fat and
CETP 16q13 rs5882 Missense variant G 0.37
TG between lipoproteins in circulation TG [108]
HDL-C bound protein that transports Total fat and HDL [109] rs9282541 Missense variant T 0.01
ABCA1 9q31.1
intracellular cholesterol onto HDL-C SFA and TG [108] rs2230806 Missense variant T 0.32
Hepatic triglyceride lipase, also involved in SFA and HDL, TG [98]; total fat and Intron variant in promotor region,
LIPC 15q21.3 rs1800588 T 0.29
lipoprotein uptake HDL [110] associated with lowered LIPC activity
Predominant apolipoprotein on HDL; SFA, total fat, and TC [108] rs670 Upstream intronic variant T 0.18
APOA1 11q23.3
activator of LCAT Total fat and HDL [108] rs5070 Intron variant G 0.44
Cellular Lipid Uptake Pathway
Present on TG-rich lipoproteins
APOE 19q13.32 Total fat, SFA, and HDL [98] rs405509 Upstream variant in promoter region T 0.47
(chylomicrons, VLDL)
Scavenger receptor, binds to oxidized LDL
CD36 7q21.11 Oily fish (n-3 PUFA) and HDL [40] rs6969989 Intron variant G 0.33
and LCFA.
Hydrolyzes TG to allow fatty acids from
LPL 8p21.3 Total fat and HDL [33,110] rs328 Nonsense variant G 0.10
lipoproteins into circulation
Lipid/Lipoprotein Formation Pathway
Present on HDL particles, stimulates LPL, Total fat and TC, LDL, HDL [96]; rs964184 3’ untranslated region (UTR) variant G 0.22
APOA5 11q23.3
major determinant of plasma TG concentrations
Total fat and TG [90] rs662799 Upstream variant in promoter region G 0.16
n-3, n-6 PUFAs and HDL [111];
FADS
11q12-13.1 Desaturation of long-chain fatty acids alpha-linolenic acid and non-HDL rs174546 3’ UTR variant T 0.28
Complex
cholesterol [112]
Activates carbohydrate-responsive element binding
MLXIPL 7q11.23 Mediterranean diet and TG [113] rs3812316 Missense variant G 0.11
protein and promotes hepatic TG synthesis
n-3 PUFA and TC, LDL rs6008259 Non-coding transcript variant A 0.32
PPARA 22q13.31 Nuclear receptor in liver, ligand for PUFAs
n-6 PUFA and TC, LDL [114] rs3892755 Non-coding transcript variant A 0.09
Nutrients 2018, 10, 1404 11 of 17

Author Contributions: Conceptualization, B.A.H.; Writing-Original Draft Preparation, B.A.H.; Writing-Review &
Editing, N.A.K. and M.T.G.; Supervision, N.A.K. and M.T.G.; All authors approved the final manuscript.
Funding: B.A.H. and M.T.G. are supported by the Agriculture and Food Research Initiative Competitive Grant no.
2015-68001-23248 from the USDA National Institute of Food and Agriculture to Cooperative Extension and the
Department of Human Development and Family Studies at the University of Illinois at Urbana-Champaign.
Support for this work also comes from Hatch Projects #ILLU-971-368, #ILLU-793-327, and the Department of
Kinesiology and Community Health at the University of Illinois at Urbana-Champaign.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Carroll, M.D.; Fryer, C.D.; Nguyen, D.T. High Total and Low High-Density Lipoprotein Cholesterol in Adults:
United States, 2015–2016; NCHS Data Brief, No 290; National Center for Health Statistics: Hyattsville, MD,
USA, 2017.
2. Eckel, R.H.; Jakicic, J.M.; Ard, J.D.; Hubbard, V.S.; de Jesus, J.M.; Lee, I.-M.; Lichtenstein, A.H.; Loria, C.M.;
Millen, B.E.; Miller, N.H.; et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce
Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. Circulation 2013, 129, S76–S99. [CrossRef] [PubMed]
3. Bamba, V. Update on screening, etiology, and treatment of dyslipidemia in children. JCEM 2014, 99,
3093–3102. [CrossRef] [PubMed]
4. Kussmann, M.; Stover, P.J. Nutrigenomics and Proteomics in Health and Disease: Towards a Systems-Level
Understanding of Gene-Diet Interactions, 2nd ed.; John Wiley & Sons: Hoboken, NJ, USA, 2017; p. 1119098831.
5. Tenenbaum, A.; Klempfner, R.; Fisman, E.Z. Hypertriglyceridemia: A too long unfairly neglected major
cardiovascular risk factor. Cardiovasc. Diabetol. 2014, 13, 159. [CrossRef] [PubMed]
6. Miller, M.; Stone, N.J.; Ballantyne, C.; Bittner, V.; Criqui, M.H.; Ginsberg, H.N.; Goldberg, A.C.; Howard, W.J.;
Jacobson, M.S.; Kris-Etherton, P.M.; et al. Triglycerides and cardiovascular disease: A scientific statement
from the American Heart Association. Circulation 2011, 123, 2292–2333. [CrossRef] [PubMed]
7. Wajchenberg, B.L. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome.
Endocr. Rev. 2000, 21, 697–738. [CrossRef] [PubMed]
8. Després, J.-P.; Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 2006, 444, 881. [CrossRef]
[PubMed]
9. Schwartz, G.G.; Olsson, A.G.; Abt, M.; Ballantyne, C.M.; Barter, P.J.; Brumm, J.; Chaitman, B.R.; Holme, I.M.;
Kallend, D.; Leiter, L.A. Effects of dalcetrapib in patients with a recent acute coronary syndrome. NEJM 2012,
367, 2089–2099. [CrossRef] [PubMed]
10. Rader, D.J.; Hovingh, G.K. HDL and cardiovascular disease. Lancet 2014, 384, 618–625. [CrossRef]
11. Marais, A.D. Familial hypercholesterolaemia. Clin. Biochem. Rev. 2004, 25, 49. [PubMed]
12. Oliva, C.P.; Pisciotta, L.; Volti, G.L.; Sambataro, M.P.; Cantafora, A.; Bellocchio, A.; Catapano, A.; Tarugi, P.;
Bertolini, S.; Calandra, S. Inherited apolipoprotein AV deficiency in severe hypertriglyceridemia. Arterioscl.
Thromb. Vasc. Biol. 2005, 25, 411–417. [CrossRef] [PubMed]
13. Tolleshaug, H.; Hobgood, K.K.; Brown, M.S.; Goldstein, J.L. The LDL receptor locus in familial
hypercholesterolemia: Multiple mutations disrupt transport and processing of a membrane receptor. Cell
1983, 32, 941–951. [CrossRef]
14. Lusis, A.J.; Fogelman, A.M.; Fonarow, G.C. Genetic basis of atherosclerosis: Part I: New genes and pathways.
Circulation 2004, 110, 1868–1873. [CrossRef] [PubMed]
15. Dron, J.S.; Hegele, R.A. Genetics of lipid and lipoprotein disorders and traits. Curr. Genet. Med. Rep. 2016, 4,
130–141. [CrossRef] [PubMed]
16. Teslovich, T.M.; Musunuru, K.; Smith, A.V.; Edmondson, A.C.; Stylianou, I.M.; Koseki, M.; Pirruccello, J.P.;
Ripatti, S.; Chasman, D.I.; Willer, C.J.; et al. Biological, clinical and population relevance of 95 loci for blood
lipids. Nature 2010, 466, 707–713. [CrossRef] [PubMed]
17. Global Lipids Genetics Consortium; Willer, C.J.; Schmidt, E.M.; Sengupta, S.; Peloso, G.M.; Gustafsson, S.;
Kanoni, S.; Ganna, A.; Chen, J.; Buchkovich, M.L.; et al. Discovery and refinement of loci associated with
lipid levels. Nat. Genet. 2013, 45, 1274. [CrossRef]
18. Fielding, C.J.; Fielding, P.E. Molecular physiology of reverse cholesterol transport. J. Lipid Res. 1995, 36,
211–228. [PubMed]
Nutrients 2018, 10, 1404 12 of 17

19. Tall, A.R. An overview of reverse cholesterol transport. Eur. Heart J. 1998, 19 (Suppl. A), A31–A35. [CrossRef]
20. Clifford, A.J.; Rincon, G.; Owens, J.E.; Medrano, J.F.; Moshfegh, A.J.; Baer, D.J.; Novotny, J.A. Single nucleotide
polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors
of plasma HDL in healthy adults. Lipids Health Dis. 2013, 12, 66. [CrossRef] [PubMed]
21. Lu, Y.; Liu, Y.; Li, Y.; Zhang, H.; Yu, M.; Kanu, J.S.; Qiao, Y.; Tang, Y.; Zhen, Q.; Cheng, Y. Association of
ATP-binding cassette transporter A1 gene polymorphisms with plasma lipid variability and coronary heart
disease risk. Int. J. Clin. Exp. Path 2015, 8, 13441–13449.
22. Mirmiran, P.; Esfandiar, Z.; Hosseini-Esfahani, F.; Koochakpoor, G.; Daneshpour, M.S.; Sedaghati-Khayat, B.;
Azizi, F. Genetic variations of cholesteryl ester transfer protein and diet interactions in relation to lipid
profiles and coronary heart disease: A systematic review. Nutr. Metab. 2017, 14, 77. [CrossRef] [PubMed]
23. Nakamura, A.; Niimura, H.; Kuwabara, K.; Takezaki, T.; Morita, E.; Wakai, K.; Hamajima, N.; Nishida, Y.;
Turin, T.C.; Suzuki, S.; et al. Gene-Gene combination effect and interactions among ABCA1, APOA1, SR-B1,
and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population. PLoS
ONE 2013, 8, e82046. [CrossRef] [PubMed]
24. Qiu, L.; Yin, R.-X.; Khounphinith, E.; Zhang, F.-H.; Yang, D.-Z.; Pan, S.-L. Association of the APOA1 rs964184
SNP and serum lipid traits in the Chinese Maonan and Han populations. Lipids Health Dis. 2018, 17, 105.
[CrossRef] [PubMed]
25. Deeb, S.S.; Zambon, A.; Carr, M.C.; Ayyobi, A.F.; Brunzell, J.D. Hepatic lipase and dyslipidemia: Interactions
among genetic variants, obesity, gender, and diet. J. Lipid Res. 2003, 44, 1279–1286. [CrossRef] [PubMed]
26. Agirbasli, M.; Eren, F.; Agirbasli, D.; White, M.J.; Williams, S.M. Multi-Locus Candidate Gene Analyses
of Lipid Levels in a Pediatric Turkish Cohort: Lessons Learned on LPL, CETP, LIPC, ABCA1, and SHBG.
OMICS J. Integr. Biol. 2013, 17, 636–645. [CrossRef] [PubMed]
27. Wang, H.; Zhang, D.; Ling, J.; Lu, W.; Zhang, S.; Zhu, Y.; Lai, M. Gender specific effect of LIPC C-514T
polymorphism on obesity and relationship with plasma lipid levels in Chinese children. J. Cell. Mol. Med.
2015, 19, 2296–2306. [CrossRef] [PubMed]
28. Xu, M.; Ng, S.S.; Bray, G.A.; Ryan, D.H.; Sacks, F.M.; Ning, G.; Qi, L. Dietary Fat Intake Modifies the Effect
of a Common Variant in the LIPC Gene on Changes in Serum Lipid Concentrations during a Long-Term
Weight-Loss Intervention Trial. J. Nutr. 2015, 145, 1289–1294. [CrossRef] [PubMed]
29. Agirbasli, D.; Cirakoglu, B.; Eren, F.; Sumerkan, M.; Aksoy, S.; Aral, C.; Agirbasli, M. Effects of lecithin:
Cholesterol acyltransferase genotypes, enzyme levels, and activity on high-density lipoprotein levels. J. Clin.
Lipid 2011, 5, 152–158. [CrossRef] [PubMed]
30. Goldberg, I.J.; Eckel, R.H.; Abumrad, N.A. Regulation of fatty acid uptake into tissues: Lipoprotein lipase
and CD36-mediated pathways. J. Lipid Res. 2009, 50, S86–S90. [CrossRef] [PubMed]
31. Silverstein, R.L.; Febbraio, M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis,
and behavior. Sci. Signal. 2009, 2, re3. [CrossRef] [PubMed]
32. Deo, R.C.; Reich, D.; Tandon, A.; Akylbekova, E.; Patterson, N.; Waliszewska, A.; Kathiresan, S.; Sarpong, D.;
Taylor, H.A.; Wilson, J.G. Genetic Differences between the Determinants of Lipid Profile Phenotypes in
African and European Americans: The Jackson Heart Study. PLoS Genet. 2009, 5, e1000342. [CrossRef]
[PubMed]
33. Ayyappa, K.A.; Shatwan, I.; Bodhini, D.; Bramwell, L.R.; Ramya, K.; Sudha, V.; Anjana, R.M.; Lovegrove, J.A.;
Mohan, V.; Radha, V.; et al. High fat diet modifies the association of lipoprotein lipase gene polymorphism
with high density lipoprotein cholesterol in an Asian Indian population. Nutr. Metab. 2017, 14, 8. [CrossRef]
[PubMed]
34. Fairoozy, R.H.; White, J.; Palmen, J.; Kalea, A.Z.; Humphries, S.E. Identification of the functional variant(s)
that explain the low-density lipoprotein receptor (LDLR) GWAS SNP rs6511720 association with lower
LDL-C and risk of CHD. PLoS ONE 2016, 11, e0167676. [CrossRef] [PubMed]
35. Gao, F.; Ihn, H.E.; Medina, M.W.; Krauss, R.M. A common polymorphism in the LDL receptor gene has
multiple effects on LDL receptor function. Hum. Mol. Genet. 2013, 22, 1424–1431. [CrossRef] [PubMed]
36. Wang, Y.; Gusarova, V.; Banfi, S.; Gromada, J.; Cohen, J.C.; Hobbs, H.H. Inactivation of ANGPTL3 reduces
hepatic VLDL-triglyceride secretion. J. Lipid Res. 2015, 56, 1296–1307. [CrossRef] [PubMed]
Nutrients 2018, 10, 1404 13 of 17

37. Legry, V.; Bokor, S.; Cottel, D.; Beghin, L.; Catasta, G.; Nagy, E.; Gonzalez-Gross, M.; Spinneker, A.; Stehle, P.;
Molnar, D.; et al. Associations between common genetic polymorphisms in angiopoietin-like proteins 3
and 4 and lipid metabolism and adiposity in European adolescents and adults. JCEM 2009, 94, 5070–5077.
[CrossRef] [PubMed]
38. Paththinige, C.S.; Sirisena, N.D.; Dissanayake, V.H.W. Genetic determinants of inherited susceptibility to
hypercholesterolemia—A comprehensive literature review. Lipids Health Dis. 2017, 16, 103. [CrossRef]
[PubMed]
39. Ma, X.; Bacci, S.; Mlynarski, W.; Gottardo, L.; Soccio, T.; Menzaghi, C.; Iori, E.; Lager, R.A.; Shroff, A.R.;
Gervino, E.V.; et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and
increased cardiovascular risk in Caucasians. Hum. Mol. Genet. 2004, 13, 2197–2205. [CrossRef] [PubMed]
40. Shin, Y.; Kim, Y. Oily Fish Consumption Modifies the Association between CD36 rs6969989 Polymorphism
and Lipid Profiles in Korean Women. Prev. Nutr. Food Sci. 2016, 21, 202–207. [CrossRef] [PubMed]
41. Ramos-Arellano, L.E.; Salgado-Bernabe, A.B.; Guzman-Guzman, I.P.; Salgado-Goytia, L.; Munoz-Valle, J.F.;
Parra-Rojas, I. CD36 haplotypes are associated with lipid profile in normal-weight subjects. Lipids Health Dis.
2013, 12, 167. [CrossRef] [PubMed]
42. Ellsworth, J.L.; Erickson, S.K.; Cooper, A.D. Very low and low density lipoprotein synthesis and secretion by
the human hepatoma cell line Hep-G2: Effects of free fatty acid. J. Lipid Res. 1986, 27, 858–874. [PubMed]
43. Hellerstein, M.K.; Schwarz, J.M.; Neese, R.A. Regulation of Hepatic De Novo Lipogenesis in Humans.
Ann. Rev. Nutr. 1996, 16, 523–557. [CrossRef] [PubMed]
44. Kathiresan, S.; Willer, C.J.; Peloso, G.M.; Demissie, S.; Musunuru, K.; Schadt, E.E.; Kaplan, L.; Bennett, D.;
Li, Y.; Tanaka, T. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 2009, 41, 56.
[CrossRef] [PubMed]
45. Raichlen, D.A.; Alexander, G.E. Exercise, APOE genotype, and the evolution of the human lifespan.
Trends Neurosci. 2014, 37, 247–255. [CrossRef] [PubMed]
46. Guardiola, M.; Ribalta, J. Update on APOA5 Genetics: Toward a Better Understanding of Its Physiological
Impact. Curr. Atheroscler. Rep. 2017, 19, 30. [CrossRef] [PubMed]
47. Keramat, L.; Sadrzadeh-Yeganeh, H.; Sotoudeh, G.; Zamani, E.; Eshraghian, M.; Mansoori, A.; Koohdani, F.
Apolipoprotein A2 -265 T>C polymorphism interacts with dietary fatty acids intake to modulate
inflammation in type 2 diabetes mellitus patients. Nutrition 2017, 37, 86–91. [CrossRef] [PubMed]
48. Zamani, E.; Sadrzadeh-Yeganeh, H.; Sotoudeh, G.; Keramat, L.; Eshraghian, M.; Rafiee, M.; Koohdani, F.
The interaction between ApoA2 -265T>C polymorphism and dietary fatty acids intake on oxidative stress in
patients with type 2 diabetes mellitus. Eur. J. Nutr. 2017, 56, 1931–1938. [CrossRef] [PubMed]
49. Bokor, S.; Dumont, J.; Spinneker, A.; Gonzalez-Gross, M.; Nova, E.; Widhalm, K.; Moschonis, G.; Stehle, P.;
Amouyel, P.; De Henauw, S.; et al. Single nucleotide polymorphisms in the FADS gene cluster are associated
with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. J. Lipid Res. 2010, 51,
2325–2333. [CrossRef] [PubMed]
50. Mathias, R.A.; Sergeant, S.; Ruczinski, I.; Torgerson, D.G.; Hugenschmidt, C.E.; Kubala, M.; Vaidya, D.;
Suktitipat, B.; Ziegler, J.T.; Ivester, P.; et al. The impact of FADS genetic variants on ω6 polyunsaturated fatty
acid metabolism in African Americans. BMC Genet. 2011, 12, 50–50. [CrossRef] [PubMed]
51. Merino, D.M.; Johnston, H.; Clarke, S.; Roke, K.; Nielsen, D.; Badawi, A.; El-Sohemy, A.; Ma, D.W.;
Mutch, D.M. Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and
Asian adults. Mol. Genet. Metab. 2011, 103, 171–178. [CrossRef] [PubMed]
52. Sone, Y.; Kido, T.; Ainuki, T.; Sonoda, M.; Ichi, I.; Kodama, S.; Sone, H.; Kondo, K.; Morita, Y.; Egawa, S.; et al.
Genetic variants of the fatty acid desaturase gene cluster are associated with plasma LDL cholesterol levels
in Japanese males. J. Nutr. Sci. Vitaminol. 2013, 59, 325–335. [CrossRef] [PubMed]
53. Vazquez-Vidal, I.; Voruganti, V.S.; Hannon, B.A.; Andrade, F.C.D.; Aradillas-Garcia, C.; Nakamura, M.T.;
Teran-Garcia, M. Serum Lipid Concentrations and FADS Genetic Variants in Young Mexican College Students:
The UP-AMIGOS Cohort Study. Lifestyle Genom. 2018, 1–9. [CrossRef]
54. Yilmaz-Aydogan, H.; Kurnaz, O.; Kucukhuseyin, O.; Akadam-Teker, B.; Kurt, O.; Eronat, A.P.; Tekeli, A.;
Bugra, Z.; Ozturk, O. Different effects of PPARA, PPARG and ApoE SNPs on serum lipids in patients with
coronary heart disease based on the presence of diabetes. Gene 2013, 523, 20–26. [CrossRef] [PubMed]
Nutrients 2018, 10, 1404 14 of 17

55. Alsaleh, A.; Frost, G.S.; Griffin, B.A.; Lovegrove, J.A.; Jebb, S.A.; Sanders, T.A.; O’Dell, S.D. PPARgamma2
gene Pro12Ala and PPARalpha gene Leu162Val single nucleotide polymorphisms interact with dietary
intake of fat in determination of plasma lipid concentrations. J. Nutrigenet. Nutrigenom. 2011, 4, 354–366.
[CrossRef] [PubMed]
56. AlSaleh, A.; Sanders, T.A.; O’Dell, S.D. Effect of interaction between PPARG, PPARA and ADIPOQ gene
variants and dietary fatty acids on plasma lipid profile and adiponectin concentration in a large intervention
study. Proc. Nutr. Soc. 2012, 71, 141–153. [CrossRef] [PubMed]
57. Aung, L.-H.-H.; Yin, R.-X.; Wu, J.-Z.; Wu, D.-F.; Wang, W.; Li, H. Association between the MLX interacting
protein-like, BUD13 homolog and zinc finger protein 259 gene polymorphisms and serum lipid levels.
Sci. Rep. 2014, 4, 5565. [CrossRef] [PubMed]
58. Bustamante, C.D.; Burchard, E.G.; De la Vega, F.M. Genomics for the world. Nature 2011, 475, 163–165.
[CrossRef] [PubMed]
59. Aguilar-Salinas, C.A.; Gomez-Perez, F.J.; Rull, J.; Villalpando, S.; Barquera, S.; Rojas, R. Prevalence of
dyslipidemias in the Mexican National Health and Nutrition Survey 2006. Salud Publica Mexico 2010, 52
(Suppl. 1), S44–S53. [CrossRef]
60. The Genomes Project Consortium; Auton, A.; Abecasis, G.R.; Altshuler, D.M.; Durbin, R.M.; Abecasis, G.R.;
Bentley, D.R.; Chakravarti, A.; Clark, A.G.; Donnelly, P.; et al. A global reference for human genetic variation.
Nature 2015, 526, 68. [CrossRef] [PubMed]
61. Posadas-Sanchez, R.; Ocampo-Arcos, W.A.; Lopez-Uribe, A.R.; Posadas-Romero, C.; Villarreal-Molina, T.;
Leon, E.A.; Perez-Hernandez, N.; Rodriguez-Perez, J.M.; Cardoso-Saldana, G.; Medina-Urrutia, A.; et al.
Hepatic lipase (LIPC) C-514T gene polymorphism is associated with cardiometabolic parameters and
cardiovascular risk factors but not with fatty liver in Mexican population. Exp. Mol. Pathol. 2015, 98, 93–98.
[CrossRef] [PubMed]
62. Weissglas-Volkov, D.; Aguilar-Salinas, C.A.; Nikkola, E.; Deere, K.A.; Cruz-Bautista, I.; Arellano-Campos, O.;
Muñoz-Hernandez, L.L.; Gomez-Munguia, L.; Ordoñez-Sánchez, M.L.; Reddy, P.M.V.L.; et al. Genomic
study in Mexicans identifies a new locus for triglycerides and refines European lipid loci. J. Med. Genet. 2013,
50, 298–308. [CrossRef] [PubMed]
63. Dainis, A.M.; Ashley, E.A. Cardiovascular Precision Medicine in the Genomics Era. JACC Basic Transl. Sci.
2018, 3, 313–326. [CrossRef] [PubMed]
64. Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; de Ferranti, S.; Despres, J.P.;
Fullerton, H.J.; Howard, V.J.; et al. Heart disease and stroke statistics—2015 update: A report from the
American Heart Association. Circulation 2015, 131, e29–e322. [CrossRef] [PubMed]
65. Chowdhury, I. Alcohol and Dyslipidemia. In Alcohol, Nutrition, and Health Consequences; Watson, R.R.,
Preedy, V.R., Zibadi, S., Eds.; Humana Press: Totowa, NJ, USA, 2013; pp. 329–339.
66. Feinman, R.D.; Volek, J.S. Carbohydrate restriction as the default treatment for type 2 diabetes and metabolic
syndrome. Scand. Cardiovasc. J. 2008, 42, 256–263. [CrossRef] [PubMed]
67. US Department of Health and Human Services. 2015–2020 Dietary Guidelines for Americans; USDA:
Washington, DC, USA, 2015.
68. Bach-Faig, A.; Berry, E.M.; Lairon, D.; Reguant, J.; Trichopoulou, A.; Dernini, S.; Medina, F.X.; Battino, M.;
Belahsen, R.; Miranda, G.; et al. Mediterranean diet pyramid today: Science and cultural updates.
Public Health Nutr. 2011, 14, 2274–2284. [CrossRef] [PubMed]
69. Willett, W.C.; Sacks, F.; Trichopoulou, A.; Drescher, G.; Ferro-Luzzi, A.; Helsing, E.; Trichopoulos, D.
Mediterranean diet pyramid: A cultural model for healthy eating. Am. J. Clin. Nutr. 1995, 61, 1402S–1406S.
[CrossRef] [PubMed]
70. De Lorgeril, M.; Salen, P.; Martin, J.-L.; Monjaud, I.; Delaye, J.; Mamelle, N. Mediterranean diet, traditional
risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon
Diet Heart Study. Circulation 1999, 99, 779–785. [CrossRef] [PubMed]
71. Estruch, R.; Ros, E.; Salas-Salvadó, J.; Covas, M.-I.; Corella, D.; Arós, F.; Gómez-Gracia, E.; Ruiz-Gutiérrez, V.;
Fiol, M.; Lapetra, J. Primary prevention of cardiovascular disease with a Mediterranean diet. NEJM 2013,
368, 1279–1290. [CrossRef] [PubMed]
72. Hannon, B.A.; Thompson, S.V.; An, R.; Teran-Garcia, M. Clinical outcomes of dietary replacement of saturated
fatty acids with unsaturated fat sources in adults with overweight and obesity: A systematic review and
meta-analysis of randomized control trials. Ann. Nutr. Metab. 2017, 71, 107–117. [CrossRef] [PubMed]
Nutrients 2018, 10, 1404 15 of 17

73. Hooper, L.; Martin, N.; Abdelhamid, A.; Davey Smith, G. Reduction in saturated fat intake for cardiovascular
disease. Cochrane Database Syst. Rev. 2015. [CrossRef] [PubMed]
74. Kris-Etherton, P.M. Monounsaturated fatty acids and risk of cardiovascular disease. Circulation 1999, 100,
1253–1258. [CrossRef] [PubMed]
75. Sacks, F.M.; Lichtenstein, A.H.; Wu, J.H.Y.; Appel, L.J.; Creager, M.A.; Kris-Etherton, P.M.; Miller, M.;
Rimm, E.B.; Rudel, L.L.; Robinson, J.G.; et al. Dietary Fats and Cardiovascular Disease: A Presidential
Advisory From the American Heart Association. Circulation 2017. [CrossRef] [PubMed]
76. Davis, C.; Bryan, J.; Hodgson, J.; Murphy, K. Definition of the Mediterranean diet: A literature review.
Nutrients 2015, 7, 9139–9153. [CrossRef] [PubMed]
77. Kastorini, C.M.; Milionis, H.J.; Esposito, K.; Giugliano, D.; Goudevenos, J.A.; Panagiotakos, D.B. The effect of
Mediterranean diet on metabolic syndrome and its components: A meta-analysis of 50 studies and 534,906
individuals. J. Am. Coll. Cardiol. 2011, 57, 1299–1313. [CrossRef] [PubMed]
78. Abdelhamid, A.S.; Martin, N.; Bridges, C.; Brainard, J.S.; Wang, X.; Brown, T.J.; Hanson, S.; Jimoh, O.F.;
Ajabnoor, S.M.; Deane, K.H.O.; et al. Polyunsaturated fatty acids for the primary and secondary prevention of
cardiovascular disease. Cochrane Databse Syst. Rev. 2018. [CrossRef] [PubMed]
79. Erkkilä, A.; de Mello, V.D.F.; Risérus, U.; Laaksonen, D.E. Dietary fatty acids and cardiovascular disease: An
epidemiological approach. Prog. Lipid Res. 2008, 47, 172–187. [CrossRef] [PubMed]
80. Siscovick, D.S.; Barringer, T.A.; Fretts, A.M.; Wu, J.H.Y.; Lichtenstein, A.H.; Costello, R.B.; Kris-Etherton, P.M.;
Jacobson, T.A.; Engler, M.B.; Alger, H.M.; et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation
and the prevention of clinical cardiovascular disease. Sci. Advis. Am. Heart Assoc. 2017, 135, e867–e884.
[CrossRef]
81. Lamarche, B.; Couture, P. Dietary fatty acids, dietary patterns, and lipoprotein metabolism. Curr. Opin.
Lipidol. 2015, 26, 42–47. [CrossRef] [PubMed]
82. Fernandez, M.L.; West, K.L. Mechanisms by which dietary fatty acids modulate plasma lipids. J. Nutr. 2005,
135, 2075–2078. [CrossRef] [PubMed]
83. Teran-Garcia, M.; Rufo, C.; Nakamura, M.T.; Osborne, T.F.; Clarke, S.D. NF-Y involvement in the
polyunsaturated fat inhibition of fatty acid synthase gene transcription. Biochem. Piophys. Res. Commun.
2002, 290, 1295–1299. [CrossRef] [PubMed]
84. Brousseau, M.E.; Ordovas, J.M.; Osada, J.; Fasulo, J.; Robins, S.J.; Nicolosi, R.J.; Schaefer, E.J. Dietary
monounsaturated and polyunsaturated fatty acids are comparable in their effects on hepatic apolipoprotein
mRNA abundance and liver lipid concentrations when substituted for saturated fatty acids in cynomolgus
monkeys. J. Nutr. 1995, 125, 425–436. [CrossRef] [PubMed]
85. Ramos-Lopez, O.; Milagro, F.I.; Allayee, H.; Chmurzynska, A.; Choi, M.S.; Curi, R.; De Caterina, R.;
Ferguson, L.R.; Goni, L.; Kang, J.X.; et al. Guide for current nutrigenetic, nutrigenomic, and nutriepigenetic
approaches for precision nutrition involving the prevention and management of chronic diseases associated
with Oobesity. Lifestyle Genom. 2017, 10, 43–62. [CrossRef] [PubMed]
86. Ordovas, J.M.; Ferguson, L.R.; Tai, E.S.; Mathers, J.C. Personalised nutrition and health. BMJ 2018, 361.
[CrossRef] [PubMed]
87. Fenech, M.; El-Sohemy, A.; Cahill, L.; Ferguson, L.R.; French, T.-A.C.; Tai, E.S.; Milner, J.; Koh, W.-P.; Xie, L.;
Zucker, M.; et al. Nutrigenetics and nutrigenomics: Viewpoints on the current status and applications in
nutrition research and practice. J. Nutrigenet. Nutrigenom. 2011, 4, 69–89. [CrossRef] [PubMed]
88. Chatterjee, C.; Sparks, D.L. Hepatic lipase, high density lipoproteins, and hypertriglyceridemia. Am. J. Pathol.
2011, 178, 1429–1433. [CrossRef] [PubMed]
89. Ordovas, J.M.; Corella, D.; Demissie, S.; Cupples, L.A.; Couture, P.; Coltell, O.; Wilson, P.W.F.; Schaefer, E.J.;
Tucker, K.L. Dietary fat intake determines the effect of a common polymorphism in the hepatic lipase gene
promoter on high-density lipoprotein metabolism: Evidence of a strong dose effect in this gene-nutrient
interaction in the Framingham study. Circulation 2002, 106, 2315–2321. [CrossRef] [PubMed]
90. Sánchez-Moreno, C.; Ordovás, J.M.; Smith, C.E.; Baraza, J.C.; Lee, Y.-C.; Garaulet, M. APOA5 gene variation
interacts with dietary fat intake to modulate obesity and circulating triglycerides in a Mediterranean
population. J. Nutr. 2011, 141, 380–385. [CrossRef] [PubMed]
91. Merched, A.J.; Chan, L. Nutrigenetics and nutrigenomics of atherosclerosis. Curr. Atheroscler. Rep. 2013, 15,
328–328. [CrossRef] [PubMed]
Nutrients 2018, 10, 1404 16 of 17

92. Tai, E.S.; Corella, D.; Demissie, S.; Cupples, L.A.; Coltell, O.; Schaefer, E.J.; Tucker, K.L.; Ordovas, J.M.
Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and
apolipoprotein C-III concentrations in the Framingham Heart Study. J. Nutr. 2005, 135, 397–403. [CrossRef]
[PubMed]
93. Lai, C.Q.; Corella, D.; Demissie, S.; Cupples, L.A.; Adiconis, X.; Zhu, Y.; Parnell, L.D.; Tucker, K.L.;
Ordovas, J.M. Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma
fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: The Framingham
Heart Study. Circulation 2006, 113, 2062–2070. [CrossRef] [PubMed]
94. Garaulet, M.; Smith, C.E.; Hernandez-Gonzalez, T.; Lee, Y.C.; Ordovas, J.M. PPARgamma Pro12Ala interacts
with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet. Mol.
Nutr. Food Res. 2011, 55, 1771–1779. [CrossRef] [PubMed]
95. Zhang, X.; Qi, Q.; Zhang, C.; Smith, S.R.; Hu, F.B.; Sacks, F.M.; Bray, G.A.; Qi, L. FTO Genotype and 2-Year
Change in Body Composition and Fat Distribution in Response to Weight-Loss Diets: The POUNDS LOST
Trial. Diabetes 2012, 61, 3005–3011. [CrossRef] [PubMed]
96. Zhang, X.; Qi, Q.; Bray, G.A.; Hu, F.B.; Sacks, F.M.; Qi, L. APOA5 genotype modulates 2-y changes in lipid
profile in response to weight-loss diet intervention: The Pounds Lost Trial. Am. J. Clin. Nutr. 2012, 96,
917–922. [CrossRef] [PubMed]
97. Corella, D.; Peloso, G.; Arnett, D.K.; Demissie, S.; Cupples, L.A.; Tucker, K.; Lai, C.Q.; Parnell, L.D.;
Coltell, O.; Lee, Y.C.; et al. APOA2, dietary fat, and body mass index: Replication of a gene-diet interaction
in 3 independent populations. Arch. Intern. Med. 2009, 169, 1897–1906. [CrossRef] [PubMed]
98. Ma, Y.; Tucker, K.L.; Smith, C.E.; Lee, Y.C.; Huang, T.; Richardson, K.; Parnell, L.D.; Lai, C.Q.; Young, K.L.;
Justice, A.E.; et al. Lipoprotein lipase variants interact with polyunsaturated fatty acids for obesity traits
in women: Replication in two populations. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 1323–1329. [CrossRef]
[PubMed]
99. Robitaille, J.; Brouillette, C.; Lemieux, S.; Perusse, L.; Gaudet, D.; Vohl, M.C. Plasma concentrations of
apolipoprotein B are modulated by a gene–diet interaction effect between the LFABP T94A polymorphism
and dietary fat intake in French-Canadian men. Mol. Genet. Metab. 2004, 82, 296–303. [CrossRef] [PubMed]
100. Smith, C.E.; Arnett, D.K.; Corella, D.; Tsai, M.Y.; Lai, C.Q.; Parnell, L.D.; Lee, Y.C.; Ordovas, J.M. Perilipin
polymorphism interacts with saturated fat and carbohydrates to modulate insulin resistance. Nutr. Metab.
Cardiovasc. Dis. 2012, 22, 449–455. [CrossRef] [PubMed]
101. Abdullah, M.M.; Jones, P.J.; Eck, P.K. Nutrigenetics of cholesterol metabolism: Observational and dietary
intervention studies in the postgenomic era. Nutr. Rev. 2015, 73, 523–543. [CrossRef] [PubMed]
102. Nuno, N.B.; Heuberger, R. Nutrigenetic associations with cardiovascular disease. Rev. Cardiovasc. Med. 2014,
15, 217–225. [PubMed]
103. de Goede, J.; Geleijnse, J.M.; Ding, E.L.; Soedamah-Muthu, S.S. Effect of cheese consumption on blood
lipids: A systematic review and meta-analysis of randomized controlled trials. Nutr. Rev. 2015, 73, 259–275.
[CrossRef] [PubMed]
104. Lordan, R.; Tsoupras, A.; Mitra, B.; Zabetakis, I. Dairy fats and cardiovascular disease: Do we really need to
be concerned? Foods 2018, 7. [CrossRef] [PubMed]
105. De Oliveira Otto, M.C.; Lemaitre, R.N.; Song, X.; King, I.B.; Siscovick, D.S.; Mozaffarian, D. Serial measures of
circulating biomarkers of dairy fat and total and cause-specific mortality in older adults: The Cardiovascular
Health Study. Am. J. Clin. Nutr. 2018, 108, 476–484. [CrossRef]
106. De Toro-Martín, J.; Arsenault, B.; Després, J.-P.; Vohl, M.-C. Precision Nutrition: A Review of Personalized
Nutritional Approaches for the Prevention and Management of Metabolic Syndrome. Nutrients 2017, 9, 913.
[CrossRef] [PubMed]
107. Ohlhorst, S.D.; Russell, R.; Bier, D.; Klurfeld, D.M.; Li, Z.; Mein, J.R.; Milner, J.; Ross, A.C.; Stover, P.;
Konopka, E. Nutrition research to affect food and a healthy lifespan. Adv. Nutr. 2013, 4, 579–584. [CrossRef]
[PubMed]
108. Rudkowska, I.; Dewailly, E.; Hegele, R.A.; Boiteau, V.; Dube-Linteau, A.; Abdous, B.; Giguere, Y.;
Chateau-Degat, M.L.; Vohl, M.C. Gene-diet interactions on plasma lipid levels in the Inuit population.
Br. J. Nutr. 2013, 109, 953–961. [CrossRef] [PubMed]
Nutrients 2018, 10, 1404 17 of 17

109. Jacobo-Albavera, L.; Posadas-Romero, C.; Vargas-Alarcón, G.; Romero-Hidalgo, S.; Posadas-Sánchez, R.;
González-Salazar, M.D.C.; Carnevale, A.; Canizales-Quinteros, S.; Medina-Urrutia, A.; Antúnez-Argüelles, E.;
et al. Dietary fat and carbohydrate modulate the effect of the ATP-binding cassette A1 (ABCA1) R230C
variant on metabolic risk parameters in premenopausal women from the Genetics of Atherosclerotic Disease
(GEA) Study. Nutr. Metab. 2015, 12, 45. [CrossRef] [PubMed]
110. Nettleton, J.A.; Steffen, L.M.; Ballantyne, C.M.; Boerwinkle, E.; Folsom, A.R. Associations between
HDL-cholesterol and polymorphisms in hepatic lipase and lipoprotein lipase genes are modified by dietary
fat intake in African American and White adults. Atherosclerosis 2007, 194, e131–e140. [CrossRef] [PubMed]
111. Lu, Y.; Feskens, E.J.; Dolle, M.E.; Imholz, S.; Verschuren, W.M.; Muller, M.; Boer, J.M. Dietary n-3 and n-6
polyunsaturated fatty acid intake interacts with FADS1 genetic variation to affect total and HDL-cholesterol
concentrations in the Doetinchem Cohort Study. Am. J. Clin. Nutr. 2010, 92, 258–265. [CrossRef] [PubMed]
112. Dumont, J.; Huybrechts, I.; Spinneker, A.; Gottrand, F.; Grammatikaki, E.; Bevilacqua, N.; Vyncke, K.;
Widhalm, K.; Kafatos, A.; Molnar, D.; et al. FADS1 genetic variability interacts with dietary alpha-linolenic
acid intake to affect serum non-HDL-cholesterol concentrations in European adolescents. J. Nutr. 2011, 141,
1247–1253. [CrossRef] [PubMed]
113. Ortega-Azorin, C.; Sorli, J.V.; Estruch, R.; Asensio, E.M.; Coltell, O.; Gonzalez, J.I.; Martinez-Gonzalez, M.A.;
Ros, E.; Salas-Salvado, J.; Fito, M.; et al. Amino acid change in the carbohydrate response element binding
protein is associated with lower triglycerides and myocardial infarction incidence depending on level of
adherence to the Mediterranean diet in the PREDIMED trial. Circ. Cardiovasc. Genet. 2014, 7, 49–58.
[CrossRef] [PubMed]
114. Volcik, K.A.; Nettleton, J.A.; Ballantyne, C.M.; Boerwinkle, E. Peroxisome proliferator–activated receptor
α genetic variation interacts with n–6 and long-chain n–3 fatty acid intake to affect total cholesterol and
LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study. Am. J. Clin. Nutr. 2008,
87, 1926–1931. [CrossRef] [PubMed]

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).